Project Summary Schizophrenia (SCZ) and Bipolar Disorder (BD) are multifactorial psychiatric disorders that are often marked by impaired functioning of the prefrontal cortex (PFC) that leads to behavioral deficits including impairments in executive functioning, such as cognitive flexibility. SCZ and BD have also been shown to have strong genetic components linking the diseases to protein-coding genes, specifically those associated with synaptic transmission and plasticity. Recently, circular RNAs (circRNAs) and other non-coding RNAs have been posited to regulate genes leading to network changes and altered functional output. Although circular RNAs are highly enriched in the mammalian brain, little is known about their functions and interactions with protein-coding genes. Our recent work demonstrates that circHomer1, a circRNA derived from the post-synaptic density gene HOMER1, is reduced in postmortem orbitofrontal cortex (OFC) samples from patients with SCZ and BD and is inversely correlated to the relative abundance of HOMER1B, a long mRNA isoform associated with neuronal hyperexcitability. Further, in vivo circHomer1 knockdown in mouse OFC increases the synaptic localization of Homer1b and in mouse neuronal cultures, loss of circHomer1 increases neuronal excitability. Preliminary data shows that loss of circHomer1 negatively impacts behavior. Mice with reduced circHomer1 expression in the OFC exhibit significant learning impairments on reversal of a learned association, similar to those seen in patients with psychiatric disorders. This project seeks to understand the mechanism of these alterations, by first testing whether circHomer1 dynamically regulates the expression of Homer1 isoforms during behavior. Next, we will test the hypothesis that reduction of aberrantly increased Homer1b after circHomer1 knockdown is sufficient to rescue reversal impairment. We will then utilize in vivo electrophysiology during reversal learning to determine whether synchronous neuronal activity within the OFC is disrupted. Finally, we will then test the hypothesis that increased excitability after loss of circHomer1 alters spike-field coupling during the reversal learning paradigm. The completion of these aims will help elucidate the mechanisms by which a circular RNA regulates mRNA expression and localization to impact neuronal activity associated with behavioral flexibility and will provide targets for future therapeutic applications for schizophrenia and bipolar disorder.